This invention relates to diagnosis and treatment of neuronal abnormalities.
The most common cause of disabling dementia in humans is Alzheimer s disease ("AD"). Its incidence increases sharply with aqe, and it is a major public health problem in our aging population. At present the by examination of brain tissue at autopsy. Human brain manipulation, as biopsy specimens are necessarily rare of the etiology of AD and of therapeutic approaches to disease are severely hampered by the absence of a known animal model.
Persons suffering from Alzheimer s disease show a characteristic neuropathology, including senile plaques and neurofibrillary tanqles. Neurofibrillary tangles comprise paired helical filaments ("PHF"), D. L. Selkoe et al., 1987, Science, vol. 235, pp. 873-76. A senile plaque commonly comprises a mass of disorganized neurites surrounding a deposit of extracellular filaments of an amyloid polypeptide (.beta. amyloid protein). D. Goldgaber et al., 1987, Science, vol. 235, pp. 877-80, and R. E. Tanzi et al., 1987, Science, vol. 235, pp. 880-84, cloned complementary DNAs for .beta. amyloid protein, and concluded that the .beta. amyloid protein gene is expressed at least at the level of mRNA in a variety of human neural and non-neural tissues. B. L. Wolozin et al., 1986, Science, vol. 232, pp. 648-50, prepared a monoclonal antibody, termed Alz-50, against homogenates of brain tissue of AD patients, that recognizes an antigen that is present in much higher concentration in certain brain regions of AD patients than in normal brain. Their data suggested that the antigen was a 68K molecular weight protein ("A-68 protein"), and that it was present in neurons involved in the formation of neuritic plagues and neurofibrillary tangles, and in some morphologically normal neurons in brains of AD patients.
A variety of cellular and molecular abnormalities are also expressed in a variety of non-neural tissues from patients having Alzheimer's disease, including cells cultured from the patient's skin. For example, C. Peterson et al., 1985, New England Jour. Med., vol. 312,pp. 1063-65, described defects in calcium homeostasis in cultured skin fibroblasts from patients with Alzheimer's disease ("AD patients") in excess of those from clinically normal subjects; C. Peterson et al., 1986, Proc. Natl. Acad. Sci. USA, vol. 83, pp. 2758-62, measured lower levels of mitochondria-dependent oxidative metabolism in cultured skin fibroblasts from AD patients than from clinically normal subjects; J. A. Kessler, 1987, Ann. Neurol., vol. 21, pp. 95-98, found lower production of a chol-inergic differentiating factor by cultured AD skin fibroblasts than by cultured normal skin fibroblasts. B. A. Malow et al., 1987, Clin. Res., vol. 35, p. 579A, described a pilot therapeutic trial showing improvement in performance by AD patients of a verbal-recall task after administration of L carnitine, and described amelioration of an abnormality in cyclic AMP production by application of L-carnitine to cultured skin fibroblasts from AD patients.
E. Yavin et al., 1986, J. Neurochem., vbl. 46, pp. 794-803, described release by PC12 pheochromocytoma cells in culture of glycoproteins, some stimulated by nerve growth factor ("NGF") and others by exogenous gangliosides in the media.